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SeSevvere sialorrhoea (ere sialorrhoea (drooling) in children anddrooling) in children andyyoung people with chronic neurologicaloung people with chronic neurologicaldisorders: ordisorders: oral glyal glycopcopyrronium bromideyrronium bromide
Evidence summary
Published: 14 February 2017nice.org.uk/guidance/es5
pat hways
KKeey pointsy points
The content of this evidence summary was up-to-date in February 2017. See summaries of
product characteristics (SPCs), British national formulary (BNF), BNF for children (BNFc) or
the MHRA or NICE websites for up-to-date information.
Regulatory status:Regulatory status: new medicine. Glycopyrronium bromide (Sialanar) is an antimuscarinic
(anticholinergic) medicine licensed in September 2016 for the symptomatic treatment of severe
sialorrhoea (chronic pathological drooling) in children and adolescents aged 3 years and older with
chronic neurological disorders. Sialanar is licensed for short-term intermittent use and is only
licensed in children. There is limited clinical trial evidence on the use of glycopyrronium in adults
with sialorrhoea. Sialanar 320 micrograms/ml oral solution is the first formulation of
glycopyrronium bromide licensed for this indication in the UK.
OvOverviewerview
This evidence summary discusses 2 small randomised controlled trials (RCTs) that compared
glycopyrronium bromide with placebo for the treatment of severe sialorrhoea in children and
young people with chronic neurological conditions. The majority of participants had cerebral palsy.
© NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and-conditions#notice-of-rights).
Page 1 of34
In both RCTs, participants treated with glycopyrronium bromide had statistically significantly
improved drooling after 8 weeks, (measured using the modified Teacher's Drooling Scale [mTDS]),
compared with placebo.
Adverse effects were common with glycopyrronium bromide, mostly due to its anticholinergic
action. The most commonly reported adverse effects include dry mouth, constipation, urinary
retention, reduced bronchial secretions and flushing. The SPC advises that glycopyrronium
bromide can cause thickening of secretions, which may increase the risk of respiratory infection
and pneumonia. Glycopyrronium bromide should be used with caution in people with heart
problems due to its potential increase in heart rate, blood pressure and rhythm disorders (SPC:
glycopyrronium).
There is a lack of long-term safety data for glycopyrronium bromide, and the SPC recommends that
the total treatment duration should be kept as short as possible.
It is not possible to determine the relative effectiveness of glycopyrronium bromide compared with
other treatments for severe sialorrhoea because glycopyrronium has only been compared to
placebo. Because Sialanar is not bioequivalent to other formulations of glycopyrronium bromide,
switching to Sialanar should only be conducted under supervision to ensure that efficacy and side
effects are balanced. The effectiveness of glycopyrronium bromide should be balanced against the
adverse effects associated with treatment.
A summary to inform local decision-making is shown in table 1.
TTableable 1 Summary of the e1 Summary of the evidence on effectivvidence on effectiveness, safetyeness, safety, patient factors and resource implications, patient factors and resource implications
EffectivEffectivenesseness
After 8 weeks treatment, oral glycopyrronium bromide significantly improved drooling,
measured using the mTDS, in children and young people with neurological conditions,
compared with placebo (2 RCTs, n=77).
One RCT had a high drop-out rate (12/39, 31%), and children who did not complete the
study were not included in the efficacy analysis, which may have introduced bias (Mier et al.
2000).
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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SafetySafety
The SPC states that adverse effects are common with glycopyrronium bromide due to its
anticholinergic action. The most common adverse reactions include dry mouth,
constipation, diarrhoea, vomiting, urinary retention, flushing and nasal congestion.
The SPC advises that anticholinergic adverse effects may be dose dependent and difficult to
assess in a child with disabilities. Treatment should be stopped in the event of constipation,
urinary retention or pneumonia.
Due to the lack of long term safety data, glycopyrronium bromide is recommended for
short-term intermittent use only.
PPatient factorsatient factors
Glycopyrronium bromide was associated with more adverse effects and discontinuations
because of adverse effects than placebo.
The SPC recommends that glycopyrronium bromide should be taken at least one hour
before or at least two hours after meals or at consistent times with respect to food intake.
Most children in the clinical trials had cerebral palsy. Glycopyrronium has not been
extensively tested in children with other neurological conditions.
Resource implicationsResource implications
Glycopyrronium bromide 400 microgram/ml oral solution (Sialanar) costs £320 per 250 ml
bottle (MIMS, February 2017). At a dose of 1,600 micrograms (4 ml) three times daily the
28-day cost is £430.08 (based on a child weighing 33 kg at a dose of 48 micrograms/kg
glycopyrronium bromide).
Once opened the bottle has a shelf life of 28 days. Any liquid remaining after this time
should be discarded.
The manufacturer estimates that there are approximately 1,500 children in England who
may be eligible for treatment with glycopyrronium bromide.
Introduction and current guidanceIntroduction and current guidance
Sialorrhoea (chronic pathological drooling) may present in children and young people with a
neurological disorder, such as cerebral palsy. Chronic drooling is the unintentional loss of saliva
from the mouth. Although drooling is normal in infants, it usually stops by 15 to 18 months, and is
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
© NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and-conditions#notice-of-rights).
Page 3 of34
considered pathological if it is present after 4 years (Zeller et al. 2012a). Drooling can result in
perioral chapping, irritation, maceration and secondary infection of the skin. The prevalence of
moderate-to-severe drooling in children, young people and adults with neurological conditions,
particularly cerebral palsy, is estimated to be between 10% and 37% (Zeller et al. 2012a; Mier et al.
2000).
The NICE guideline on cerebral palsy in under 25s recommends considering anticholinergic
medication to reduce the severity and frequency of drooling in children and young people with
cerebral palsy. The guideline recommends glycopyrronium bromide (oral or by enteral tube),
transdermal hyoscine hydrobromide or trihexyphenidyl hydrochloride (for children with dyskinetic
cerebral palsy, but only with input from specialist services).
Product oProduct ovverviewerview
Mode of action
Glycopyrronium bromide is an antimuscarinic (anticholinergic) medicine that reduces salivary
secretions. It has limited ability to penetrate the blood brain barrier, although the extent of
penetration is unknown (SPC: glycopyrronium).
Regulatory status
Glycopyrronium bromide (Sialanar) received a European marketing authorisation in September
2016 and was launched in the UK in January 2017. Each millilitre (ml) of Sialanar 320 micrograms/
ml oral solution contains 400 micrograms glycopyrronium bromide. Glycopyrronium bromide
400 microgram/ml oral solution is licensed for the symptomatic treatment of severe sialorrhoea
(chronic pathological drooling) in children and adolescents aged 3 years and older with chronic
neurological disorders (SPC: glycopyrronium).
Although glycopyrronium bromide is used in clinical practice, Sialanar is the first preparation
licensed for this indication in the UK. Previously, people requiring treatment with glycopyrronium
bromide have used imported products (including the US product Cuvposa) or formulations made by
specials manufacturers. The different formulations of glycopyrronium bromide are not
bioequivalent (see dosing information).
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Dosing information
The SPC states that each millilitre (ml) of oral solution contains 400 micrograms of glycopyrronium
bromide, equivalent to 320 micrograms of glycopyrronium. Care should be taken when calculating
the dose of Sialanar, with particular attention to whether the dose is expressed as glycopyrronium
or glycopyrronium bromide. The dosing schedule is based on the weight of the child, starting with
approximately 12.8 micrograms/kg glycopyrronium per dose (equivalent to 16 micrograms/kg of
glycopyrronium bromide per dose) three times daily and increasing the dose every 7 days using the
dosing table (see table 1 in the SPC).
Dose titrations should be carried out in discussion with the parent or carer to assess both efficacy
and adverse effects until an acceptable maintenance dose is achieved. The maximum single dose is
64 micrograms/kg body weight of glycopyrronium or 6 ml (1,900 micrograms glycopyrronium,
equivalent to 2,400 micrograms glycopyrronium bromide) three times daily, whichever dose is less
(SPC: glycopyrronium).
Food reduces the absorption of glycopyrronium bromide, and the SPC advises that it should be
taken at least 1 hour before food or at least 2 hours after meals, or at consistent times with respect
to food intake. Specialists involved in developing this evidence summary advised that this dosing
regimen may be challenging in children requiring assisted feeding or in those with a gastrostomy,
and particular care should be taken when determining the most effective dosing regimen for these
children.
In children and young people with mild to moderate renal impairment (eGFR 30–90 ml/min/
1.73m2) the dose should be reduced by 30% (see dosing table 2 in the SPC).
The EPAR for Sialanar reports on a bioavailability study conducted by the manufacturer in healthy
adults. It found that Sialanar is approximately 25% more bioavailable compared with Cuvposa, the
glycopyrronium bromide formulation licensed in the US and used in 2 studies by Zeller et al (2012a
and 2012b). Because of the difference in bioavailability the dose of Sialanar is approximately 20%
lower than the recommended dose of the Cuvposa.
Cost
The company has advised that Sialanar costs £320.00 for a 250 ml bottle (MIMS, February 2017).
The manufacturer estimates that the average dosage of glycopyrronium bromide is likely to be
1,600 microgram (4 ml) three times daily. This equates to a 28-day cost of £430.08.
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
© NICE 2018. All rights reserved. Subject to Notice of rights (https://www.nice.org.uk/terms-and-conditions#notice-of-rights).
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Once opened a bottle of Sialanar has a shelf life of 28 days. Any liquid remaining after this time
should be discarded.
Evidence reEvidence reviewview
A literature search was conducted which identified 62 references (see search strategy for full
details). These references were screened using their titles and abstracts and 11 references were
obtained and assessed for relevance.
Two randomised controlled trials (RCTs) identified from the search (Mier et al. 2000 and Zeller et
al. 2012a) were included in this evidence summary. A summary of the included studies is shown in
table 2 (see evidence tables for full details).
TTableable 2 Summary of included studies2 Summary of included studies
StudyStudy PPopulationopulation IntervIntervention andention and
comparisoncomparison
Primary outcomePrimary outcome
Mier et
al.
(2000)
RCT
Children and young people (aged
4 years and over) with
neurological conditions and
severe sialorrhoea (n=39)
Glycopyrronium
bromide vs.
placebo (cross-
over study)
Change in mean mTDS score,
from baseline to maximum
(best) scorea
Zeller
et al.
(2012a)
RCT
People aged 3 to 23b years with
cerebral palsy or another
neurological condition and severe
sialorrhoea (n=38)
Glycopyrronium
bromide (n=20)
vs. placebo
(n=18)
Responder rate (percentage
of patients with an
improvement of 3 points or
more in mTDS score)
a The authors do not explicitly state that this is this is the primary outcome of the study,
although this is reported first in the paper.b After randomisation the study protocol was amended, with a revised upper age limit of
16 years. Two participants were over 16 years and excluded from the efficacy analysis.
AbbreAbbreviations:viations:
RCT, Randomised controlled trial; mTDS, modified Teachers Drooling Scale.
The remaining 8 references were excluded. These are listed in excluded studies with reasons for
their exclusion.
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Clinical effectiveness
This evidence summary is based on 2 double-blind, placebo-controlled RCTs of children and young
people with chronic neurological disorders and severe sialorrhoea (defined in Zeller et al. 2012a as
drooling in the absence of treatment such that clothing became damp approximately 5 to 7 days
per week). Both studies had an 8 week treatment duration, which included a 4 week dose titration
phase.
The formulations of glycopyrronium bromide used in the 2 RCTs were not the new licensed
formulation of glycopyrronium bromide (Sialanar). However, in line with Article 10(a) of Directive
2001/83/EC, license applications for a medicine that has a well-established use with a recognised
efficacy and safety profile, can be supported by a bibliographic application that does not require the
manufacturer to carry out new clinical trials with their formulation of the drug (EPAR:
glycopyrronium).
Mier et al. (2000)Mier et al. (2000)
Mier et al. (2000) was a dose-ranging, crossover RCT in 39 children and young people aged 4 to
19 years with neurological conditions and severe sialorrhoea. Participants were randomised to
8 weeks of oral glycopyrronium bromide capsules or placebo capsules 3 times daily. This was
followed by a 1-week washout period and a second 1-week observation period, then a crossover to
8 weeks of the alternative intervention.
The initial glycopyrronium bromide dose was based on the participant's weight, and increased
weekly over 4 weeks. Doses were increased according to a pre-defined schedule unless adverse
effects occurred or desired 'dryness' (defined by the parent or carer) occurred. The maximum
tolerated dose was then continued for a further 4 weeks.
Over 8 weeks there was a statistically significant improvement in the primary outcome of mean
modified Teacher's Drooling Scale (mTDS) score with glycopyrronium bromide (from a mean
baseline score of 7.52 to a maximum [best] mean score of 1.85) compared with placebo (from a
score of 7.44 to 6.33), with a difference between groups of 4.48 points (p<0.001, 95% confidence
interval [CI] not reported).
Glycopyrronium bromide appeared to have a dose–response relationship, with participants on the
lowest doses of glycopyrronium bromide at the end of the study having the highest mTDS score
(indicating more severe drooling), while participants on the higher doses had lower mTDS scores.
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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ZZeller et al. (2012a)eller et al. (2012a)
Zeller et al. (2012a) was an RCT in 38 people aged 3 to 23 years with cerebral palsy or another
neurological condition, and severe sialorrhoea. Participants were randomised to 8 weeks of 3 times
daily glycopyrronium bromide oral solution or placebo oral solution. The initial glycopyrronium
bromide dose was based on weight and increased weekly for 4 weeks until the optimal tolerated
response was achieved. Participants then continued on the same dose for a further 4 weeks.
After 8 weeks there was a statistically significant improvement in the primary outcome of
'responder rate' (the proportion of participants with an improvement of at least 3 points in mTDS
score with glycopyrronium bromide (14/19, 73.7%) compared with placebo (3/17, 17.6%, p=0.001).
A statistically significant difference in responder rate was also observed after 2 weeks treatment in
the glycopyrronium bromide group (52.6%) compared with the placebo group (0%, p=0.0007).
Mean improvements in mTDS score at 8 weeks were statistically significantly greater with
glycopyrronium bromide (3.94 points, 95% CI 2.97 to 4.91) compared with placebo (0.71 points,
95% CI −0.43 to 1.84, p<0.0001), with a difference between groups of 3.23 points.
Statistically significant differences were observed for the global assessments of study medication
by investigators and parents or carers. In the glycopyrronium bromide group 84.2% of investigators
and 100% of parents or carers felt that the treatment was worthwhile, compared with 41.2% of
investigators (p=0.014) and 56.3% of parent or carers in the placebo group (p=0.0017).
An overview of the results for clinical effectiveness can be found in results tables.
Safety and tolerability
The SPC advises that glycopyrronium bromide is contraindicated in children and young people with
glaucoma, urinary retention, severe renal impairment, a history of intestinal obstruction, ulcerative
colitis, paralytic ileus, pyloric stenosis and myasthenia gravis. Concomitant treatment with oral
forms of potassium chloride and other anticholinergics is also contraindicated (SPC:
glycopyrronium).
The SPC reports that adverse effects are common with glycopyrronium bromide due to its
anticholinergic effects. The SPC states that the most common anticholinergic adverse effects in the
RCTs were dry mouth, constipation, diarrhoea and vomiting, all occurring at a rate of 15% or higher.
Other common anticholinergic symptoms include urinary retention, flushing and nasal congestion.
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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The SPC advises that anticholinergic effects may be dose dependent and difficult to assess in a child
with disabilities. Monitoring by clinicians and carers is required, and the parent or carer should stop
treatment and seek advice from the prescriber in the event of:
constipation
urinary retention
pneumonia
allergic reaction
pyrexia
very hot weather
changes in behaviour.
After evaluation of the adverse effect, a decision should be made about whether glycopyrronium
bromide should be discontinued or restarted at a lower dose.
The EPAR notes that central nervous system effects have been reported with glycopyrronium
bromide. The clinical significance of this in children with neurological disorders is uncertain. In
addition, the EPAR states that there is no information on neurodevelopment or growth in children,
which may be affected, particularly when treatment is taken long-term or in repeated episodes.
The EPAR states that it is uncertain whether the plasma concentration of glycopyrronium bromide
in children and young people with neurological conditions would have a clinically relevant effect on
blood pressure or heart rate. This means there is uncertainty about the cardiovascular safety of
glycopyrronium bromide in this population. The SPC advises caution in children with acute
myocardial infarction, hypertension, coronary artery disease, cardiac arrhythmias and conditions
characterised by tachycardia. The parent or carer should be advised to measure the pulse rate if the
child seems unwell and report a very fast or very slow heart rate.
The EPAR also notes that pneumonia appears to be associated with glycopyrronium bromide use,
although there is insufficient information on the severity of this adverse effect. Glycopyrronium
bromide can dry bronchial secretions and cause the formation of thick mucus, especially when
given at inappropriate doses, which may increase the risk of a person developing pneumonia.
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Page 9 of34
The SPC notes that reduced salivation can increase the risk of oral cavities and periodontal
diseases, and it is important that people treated with glycopyrronium bromide receive adequate
daily dental hygiene and regular dental health checks.
In Mier et al. 2000 adverse effects were reported for 25 out of 36 participants (69%) while taking
glycopyrronium bromide compared with 5 out of 30 participants (17%) while taking placebo (no
statistical analysis reported). Four of the 7 participants who dropped out while taking
glycopyrronium bromide did so before the end of the first week while on the lowest dose. More
participants experienced adverse effects as the dose increased, with only 14% of participants
reporting adverse events at the lowest dose, compared with 81% at the highest dose. No hospital
admissions or deaths were reported.
In Zeller et al. (2012a), adverse effects occurring during treatment were reported in all (20/
20; 100%) participants receiving glycopyrronium bromide compared with 15 out of 18 (83.3%)
receiving placebo (no statistical analysis reported). Four people (20%) in the glycopyrronium
bromide group had at least 1 severe adverse effect occurring during treatment compared with
none in the placebo group.
The SPC notes that published safety data are not available beyond 24 weeks treatment duration.
Given the limited long-term safety data and the uncertainties around the potential risk of
carcinogenicity, the SPC advises that the total treatment duration should be kept as short as
possible.
An overview of the results for safety and tolerability can be found in results tables.
Evidence strengths and limitations
Two double-blind, placebo-controlled RCTs were identified as relevant, evaluating the efficacy of
oral glycopyrronium bromide for treating severe sialorrhoea in children and young people with a
neurological condition (Mier et al. 2000 and Zeller et al. 2012a). Neither of the RCTs described
allocation concealment. In addition, no description of the randomisation method was provided in
Mier et al. (2000).
Zeller et al. (2012a) used a modified intention to treat (ITT) analysis, defined as all randomised
participants who were within the age range of the final amended protocol and received at least
1 dose of study treatment, with lowest rank observations carried forward for any participants who
dropped out of the study.
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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In Mier et al. (2000), efficacy analyses were not based on the ITT population, but on the population
of participants who completed the study. The authors do not describe this population in detail and
no account is given for the participants who dropped out. By not including participants who
dropped out of the study in the efficacy analysis, the investigators may have introduced bias. For
example, if participants had dropped out because of lack of effectiveness, excluding these people
from the analysis could result in an overestimate of the effectiveness of the treatment. The EPAR
reports that the company presented an analysis of all 39 randomised participants, using a baseline
observation carried forward approach for the 12 people who did not complete the study. This
analysis reduced the treatment effect from an improvement of 4.56 points in mTDS score to 3.06
points, but it is not clear whether the difference between groups remained statistically significant.
Furthermore, the EPAR states that the statistical tests used in Mier et al. (2000) were sub-optimal
for a cross-over study, noting that the standard test would be analysis of variance (ANOVA).
Both trials used the efficacy outcome measure of mTDS, a 9-point drooling rating scale that was
reported by the person, parent or carer as a measure of the severity and frequency of drooling. No
objective measure was used to quantify the amount of drooling in any of the trials. The subjective
nature of this outcome evaluation is a limitation of all the studies.
The 2 RCTs were short-term, with a treatment duration of 8 weeks. They do not provide evidence
for the safety and efficacy of long-term use of glycopyrronium bromide for managing severe
sialorrhoea in children and young people. In a longer open-label non-randomised study (Zeller et al.
2012b) 52.3% (95% CI 43.7% to 60.9%) of participants responded to treatment (improvement of
≥3 points in mTDS score) at 24 weeks. However, as this study did not include a placebo group, firm
conclusions on the long-term effectiveness of glycopyrronium bromide cannot be drawn.
In addition, both RCTs were small, including 40 or fewer participants, and neither study reports
whether a power calculation was carried out to support the small sample size.
There was also variation in the severity of the different neurological conditions among participants.
Most of the participants in the studies had cerebral palsy so it is difficult to assess the effectiveness
or safety of glycopyrronium bromide in children and young people with a neurological condition
other than cerebral palsy. However, cerebral palsy is the most common cause of physical disability
in children and young people in the developed world.
Glycopyrronium bromide has not been compared to other active treatments for severe sialorrhoea
in a published study. However, the EPAR advises that the choice of comparator was supported since
no other medicine for severe sialorrhoea has been extensively authorised in the European Union.
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Page 11 of34
In both RCTs previous use of glycopyrronium bromide was permitted, which may have introduced
bias. However, the EPAR notes that in Zeller et al. 2012a the number of participants who had
previously taken glycopyrronium bromide was similar between treatment groups, and in Mier et al.
(2000) only 5 people had been treated previously. In Mier et al. (2000), most parents indicated that
they knew when their child was receiving glycopyrronium bromide because of the improvement in
drooling. This could have biased both the efficacy results and the reporting of adverse effects.
In Zeller et al. (2012a), because children and young people receiving placebo would be expected to
continue drooling chronically, parents and carers were specifically encouraged to keep them in the
study until at least the end of the 4-week titration period.
An overview of the quality assessment of each included study can be found in evidence tables.
Estimated impact for the NHSEstimated impact for the NHS
Other treatments
Other medicines that have been used to manage sialorrhoea include the following (Specialist
Pharmacy Service, 2015):
other antimuscarinic medicines (for example hyoscine hydrobromide, amitriptyline, atropine
and trihexyphenidyl hydrochloride)
beta-blockers (for example, propranolol)
botulinum toxin.
None of these medicines are licensed in the UK for managing sialorrhoea and their use would be
off-label.
Costs of other treatments
See table 3 for the costs of other treatments in comparison to Sialanar.
TTableable 3 Costs of other treatments3 Costs of other treatments
MedicineMedicine Usual doseUsual doseaa 28-da28-day costy cost
((eexxcluding Vcluding VAAT)T)
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Page 12 of34
Glycopyrronium bromide 400 micrograms/ml
oral solution (Sialanar)
1,600 micrograms (4 ml)
three times daily
£430.08b
Hyoscine hydrobromide 150 microgram
tablets (Kwells Kids)c
150 micrograms three
times daily
£11.69d
Hyoscine hydrobromide 1.5 mg/72 hours
patches (Scopoderm)c
Apply every 72 hours £23.19d
a Doses shown do not represent the full range that can be used and do not imply therapeutic
equivalence.b Costs based on MIMS, February 2017; excluding VAT.c Not licensed for the treatment of sialorrhoea; use would be off-label.d Costs based on Drug Tariff, January 2017; excluding VAT.
Current or estimated usage
Proveca, the manufacturer of glycopyrronium bromide (Sialanar) estimates that there are
approximately 18,595 children in England with cerebral palsy, of whom 15% (2,789 children) are
estimated to have severe sialorrhoea. The manufacturer estimates that about 55% of these
children will be eligible for treatment, giving a potential treated population of 1,534 children.
Likely place in therapy
The NICE guideline on cerebral palsy in under 25s recommends considering anticholinergic
medication to reduce the severity and frequency of drooling in children and young people with
cerebral palsy. The guideline recommends glycopyrronium bromide (oral or by enteral tube),
transdermal hyoscine hydrobromide or trihexyphenidyl hydrochloride (for children with dyskinetic
cerebral palsy, but only with input from specialist services).
The results of the 2 RCTs in this evidence summary involving a total of 77 children and young
people with neurological conditions and severe sialorrhoea found after 8 weeks treatment
glycopyrronium bromide reduced drooling (measured using the modified Teacher's Drooling Scale
[mTDS]) compared with placebo. There are no studies supporting the chronic use of
glycopyrronium bromide for this indication, and the maximum duration of treatment is 24 weeks
(EPAR: glycopyrronium). Adverse effects are more common in people treated with glycopyrronium
bromide compared with placebo. Many adverse effects are due to glycopyrronium bromide's
anticholinergic action, which include dry mouth, constipation, diarrhoea and urinary retention.
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Anticholinergic effects are common with glycopyrronium bromide, may be dose dependent and
difficult to assessment in a disabled child (SPC: glycopyrronium).
The majority of participants in the 2 RCTs had cerebral palsy, it is not known if the efficacy and
safety results observed in these people will be the same in children with other neurological
conditions. Although some participants in the 2 RCTs had previously received medicines to treat
sialorrhoea, including glycopyrronium bromide, details of the treatments are not provided. It is not
known whether glycopyrronium bromide is an effective treatment for people who have failed to
respond to other treatments.
Glycopyrronium bromide oral solution is the first and only medicine licensed in the UK for the
symptomatic treatment of severe sialorrhoea (chronic pathological drooling) in children and
adolescents aged 3 years and older with chronic neurological disorders. Sialanar is only licensed in
children, there is limited clinical trial evidence on the use of glycopyrronium in adults with
sialorrhoea. Although glycopyrronium bromide has been used in the UK for many years for this
indication, this has been through the use of unlicensed products or preparations made by specials
manufacturers. The General Medicine Council's good practice guidelines recommends that
prescribers should usually prescribe medicines in accordance with the terms of their license, and
that the use of unlicensed medicines should generally be limited to when there is no suitable
licensed medicine.
Despite glycopyrronium bromide being used for many years in the UK, the EPAR highlights that it
has been primarily used in adults, in both acute and chronic settings and in formulations than
Sialanar. The adverse effect profile established in other populations cannot be applied to children
with chronic neurological disorders, many of whom have multimorbidity. In addition, each
formulation of glycopyrronium bromide has its own bioavailability profile. Sialanar is not
bioequivalent to other formulations of glycopyrronium bromide and switching to Sialanar should
only be conducted under supervision to ensure that efficacy and side effects are balanced.
The 2 RCTs measured patient-oriented primary outcomes that reported on improvements in
drooling, although neither study measured quality of life. The EPAR summarises the results of a
mapping exercise that estimated the effect of drooling on quality of life in people with cerebral
palsy. The EPAR concluded that quality of life was clearly affected in children with cerebral palsy
who had a drooling problem, compared with children who did not drool.
It is not possible to determine the relative effectiveness of glycopyrronium bromide compared with
other treatments for severe sialorrhoea because glycopyrronium bromide has only been compared
to placebo in all published RCTs. In Zeller et al. (2012a) participants treated with glycopyrronium
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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bromide had a mean mTDS score of approximately 7 at baseline (severe symptoms- drools to the
extent that clothing becomes damp; frequently), which improved after 8 weeks treatment to a
score of approximately 3 (mild symptoms- only the lips are wet; frequently). The effectiveness of
glycopyrronium bromide should be balanced against the adverse effects associated with the
treatment (EPAR: glycopyrronium).
Information for the public about medicinesInformation for the public about medicines
Evidence summaries provide an overview of the best evidence that is available about specific
medicines. They also give general information about the condition that the medicine might be
prescribed for, how the medicine is used, how it works, and what the aim of treatment is.
Evidence summaries aim to help healthcare professionals and patients decide whether medicines
are safe to use and if they are likely to work well, especially when there isn't another suitable
medicine that has a licence for the condition. They don't contain recommendations from NICE on
whether the medicine should be used.
Information about licensing of medicines
In the UK, medicines need to have a licence before they can be widely used. To get a licence, the
manufacturer of the medicine has to provide evidence that shows that the medicine works well
enough and is safe enough to be used for a specific condition and for a specific group of patients,
and that they can manufacture the medicine to the required quality. Evidence summaries explain
whether a medicine has a licence, and if it does what the licence covers.
There is more information about licensing of medicines on NHS Choices.
Medicines can be prescribed if they don't have a licence (unlicensed) or for 'off-label' use. Off-label
means that the person prescribing the medicine wants to use it in a different way than that stated
in its licence. This could mean using the medicine for a different condition or a different group of
patients, or it could mean a change in the dose or that the medicine is taken in a different way. If a
healthcare professional wants to prescribe an unlicensed medicine, or a licensed medicine off-label,
they must follow their professional guide, for example for doctors the General Medical Council's
good practice guidelines. These include giving information about the treatment and discussing the
possible benefits and harms so that the person has enough information to decide whether or not to
have the treatment. This is called giving informed consent.
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Questions that might be useful to ask about medicines
Why am I being offered this medicine?
Why am I being offered a medicine that is unlicensed or is being used off-label?
What does the treatment involve?
What are the benefits I might get?
How good are my chances of getting those benefits?
Could having the treatment make me feel worse?
Are there other treatments I could try?
What are the risks of the treatment?
Are the risks minor or serious? How likely are they to happen?
What could happen if I don't have the treatment?
ReleRelevance to other NICE progrvance to other NICE programmesammes
This use of glycopyrronium bromide is not appropriate for referral for a NICE technology appraisal
and is not currently planned into any other work programme.
The NICE guideline on cerebral palsy in under 25s recommends considering anticholinergic
medication to reduce the severity and frequency of drooling in children and young people with
cerebral palsy. The guideline recommends glycopyrronium bromide (oral or by enteral tube),
transdermal hyoscine hydrobromide or trihexyphenidyl hydrochloride (for children with dyskinetic
cerebral palsy, but only with input from specialist services).
NICE has issued a guideline on spasticity in under 19s. This guideline does not make
recommendations on the management of sialorrhoea.
The NICE evidence summary on hypersalivation: oral glycopyrronium bromide discusses the use of
glycopyrronium bromide in adults with Parkinson's disease and in adults with schizophrenia and
clozapine-induced hypersalivation (unlicensed indications).
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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ReferencesReferences
Mier RJ, Bachrach SJ, Lakin RC et al. (2000) Treatment of sialorrhea with glycopyrrolate: a double-
blind, dose-ranging study. Archives of Pediatrics and Adolescent Medicine 154: 1214–8
Zeller RS, Lee HM, Cavanaugh PF et al. (2012a) Randomized phase III evaluation of the efficacy and
safety of a novel glycopyrrolate oral solution for the management of chronic severe drooling in
children with cerebral palsy or other neurologic conditions. Therapeutics and Clinical Risk
Management 8: 15–23
Zeller RS, Davidson J, Lee HM et al. (2012b) Safety and efficacy of glycopyrrolate oral solution for
management of pathologic drooling in pediatric patients with cerebral palsy and other neurologic
conditions. Therapeutics and Clinical Risk Management 8: 25–32
Evidence tablesEvidence tables
TTable 4 Mier et al. (2000)able 4 Mier et al. (2000)
StudyStudy
referencereference
Mier RJ, Bachrach SJ, Lakin RC et al. (2000) Treatment of sialorrhea with
glycopyrrolate: a double-blind, dose-ranging study. Archives of Pediatrics and
Adolescent Medicine 154: 1214–8
UniqueUnique
identifieridentifier
Not known
Study typeStudy type RCT
Aim of theAim of the
studystudy
To evaluate the efficacy and safety of glycopyrronium bromide in the
treatment of children with developmental disabilities with sialorrhoea
Study datesStudy dates Not stated in the published study. The EPAR reports that the study was
conducted from 1998 to 1999
SettingSetting US (2 centres)
Number ofNumber of
participantsparticipants
n=39 randomised (27 included in efficacy analysis)
PPopulationopulation Children and young people aged 4 years and older (mean age 10 years
9 months) with neurodevelopmental conditions and severe sialorrhoeaa
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InclusionInclusion
criteriacriteria
Children aged 4 years and older, with neurodevelopmental conditions and
severe sialorrhoea
ExExclusionclusion
criteriacriteria
Not reported
IntervIntervention(s)ention(s) 2 dosing regimens of glycopyrronium bromide capsulesb, based on the weight
of the child:
<30 kg: 0.6 mg three times daily, increased weekly by 0.6 mg up to 2.4 mg
at week 4
>30 kg: 1.2 mg three times daily, increased weekly by 0.6 mg to 3.0 mg at
week 4
The maximum tolerated doses were then continued for a further 4 weeks.
Doses were increased according to this schedule unless adverse effects
occurred or desired 'dryness' (defined by the parent or carer) occurredc,d
ComparComparator(s)ator(s) Placebob
LLength ofength of
follow-upfollow-up
8 week treatment phase.
A cross-over design was used: the initial 8 week treatment phase was
followed by a 1 week washout period, a 1 week observation period and then 8
weeks of the alternative intervention
Primary outcomee,f:
Change in mean mTDS score from baseline to mean maximum (best) score,
over 8 weeks
OutcomesOutcomes
Secondary outcomese:
Mean mTDS score after 4 weeks at highest dose by dose level
Proportion of patients with ≥4-point improvement in mean mTDS score by
dose level
Parent or carer assessment of drooling odour
Parent or carer assessment of dryness of clothing
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Safety outcomes:
Any adverse events
Adverse events requiring treatment withdrawal
Source ofSource of
fundingfunding
Not reported
Did the trial address a clearly focused issue? Yes
Was the assignment of patients to treatments randomised? Unclearg
Were patients, health workers and study personnel blinded? Yesh
Were the groups similar at the start of the trial? Uncleari
Aside from the experimental intervention, were the groups
treated equally?
Yes
Were all of the patients who entered the trial properly accounted
for at its conclusion?
Yes
How large was the treatment effect? See table
6
How precise was the estimate of the treatment effect? See table
6
Can the results be applied in your context? (or to the local
population)
Yesj
Were all clinically important outcomes considered? Yes
OvOvererall risk ofall risk of
bias/qualitybias/quality
assessment –assessment –
CASP RCT
checklist
Are the benefits worth the harms and costs? See key
points
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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StudyStudy
limitationslimitations
Short-term study (8 weeks)
Only participants who completed the study were included in the analysis.
A high proportion of the participants did not complete the study (12/39,
31%)
The study did not include an active comparator
The study did not report on randomisation and blinding methods
It is unclear whether allocation was concealed
CommentsComments a 34/39 participants had cerebral palsy and 2/39 had tracheostomies (1 of
whom dropped out of the study because of excessively thick secretions). 5/39
participants had previously received treatment for sialorrhoea, 3 of whom
had taken glycopyrronium bromide and had stopped treatment because of
adverse effects.b Capsules were specially compounded from oral glycopyrronium bromide.
Placebo capsules were compounded using identical gelatin capsules.c The mean highest dose of glycopyrronium bromide for children who
completed the study was 2.49 mg (range 1.2–3.0 mg) per dose.d 4 participants were given these doses twice rather than three times a day, at
the parent's request.e The authors do not specify which outcomes are primary and which are
secondary, although mean change in mTDS is reported first in the paper.f Drooling was assessed weekly in the afternoon (2 hours after a dose) by
parents or carers using mTDS.g Randomisation method and allocation concealment not described.h Although the study stated that it was double-blind, it was not clear if both
investigators and clinicians providing care were blinded.i Baseline characteristics not reported.j The study population that completed the trial is not described in detail, and
no account is given for the subjects who dropped out.
AbbreAbbreviations:viations: EPAR, European Public Assessment Report; mTDS, Modified Teacher's
Drooling Scale; RCT, randomised controlled trial.
TTable 5 Zable 5 Zeller et al. 2012aeller et al. 2012a
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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StudyStudy
referencereference
Zeller RS, Lee HM, Cavanaugh PF et al. (2012a) Randomized phase III
evaluation of the efficacy and safety of a novel glycopyrrolate oral solution for
the management of chronic severe drooling in children with cerebral palsy or
other neurologic conditions. Therapeutics and Clinical Risk Management 8:
15–23
UniqueUnique
identifieridentifier
NCT00425087
Study typeStudy type RCT
Aim of theAim of the
studystudy
To assess the efficacy and safety of glycopyrronium bromide oral solution in
managing problem drooling associated with cerebral palsy and other
neurologic conditions in children
Study datesStudy dates November 2002 to April 2007
SettingSetting US (10 centres)
Number ofNumber of
participantsparticipants
n=38 randomised
PPopulationopulation People aged 3 to 23 yearsa with cerebral palsy or another neurological
condition, and problem droolingb. The mean age was approximately 9.5 years;
22/36 (61%) were male
InclusionInclusion
criteriacriteria
Male and female patients weighing at least 27 lb (12.2 kg) and previously
diagnosed with cerebral palsy, mental retardation, or another neurologic
condition associated with problem drooling were eligible. People with oral
feeding problems or who used a tube for feeding were included
ExExclusionclusion
criteriacriteria
Patients were excluded if their extent of drooling was wetness of the lips and
chin but their clothes did not become damp on most days; if they had used
glycopyrronium bromide liquid within approximately 24 hours of baseline; if
they had used any anticholinergic or cholinergic medications prohibited by
the protocol within 3 plasma half-lives of that medication prior to baseline; or
if they had medical conditions contraindicating anticholinergic therapy or
treatment with the study medication
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IntervIntervention(s)ention(s) Glycopyrronium bromide (glycopyrrolate) oral solutionc, three times
daily,with the dose titrated up weekly to the optimal tolerated doseb.
There were 5 dose levels:
0.02 mg/kg three times a day
0.04 mg/kg three times a day
0.06 mg/kg three times a da
0.08 mg/kg three times a day
0.10 mg/kg three times a day
The maximum dose was 1.5–3.0 mg three times a day (based on weight).
After the optimal dose level was reached, patients continued to receive the
same medication and dose for a total of 8 weeks
ComparComparator(s)ator(s) Placebo
LLength ofength of
follow-upfollow-up
8 weeks (including 4-week dose titration phase)
Primary outcome:
Responder rate, defined as percentage of patients with an improvement of
3 points or more in mTDS score
OutcomesOutcomes
Secondary outcomes:
Mean improvement in mTDS score at 8 weeks
Daily mean parent/carer mTDS scores at weeks 2, 4, and 6
AUC analysis of all mTDS evaluations from screening to week 8
Proportion of patients who discontinued treatment due to lack of efficacy
Proportion of investigators who considered treatment worthwhiled
Proportion of parents/carers who considered treatment worthwhiled
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Safety outcomes:
Any adverse events
All assessed at baseline and at week 8 or study discontinuation
Source ofSource of
fundingfunding
Shionogi Inc.
Did the trial address a clearly focused issue? Yes
Was the assignment of patients to treatments randomised? Uncleare
Were patients, health workers and study personnel blinded? Unclearf
Were the groups similar at the start of the trial? Yes
Aside from the experimental intervention, were the groups
treated equally?
Yes
Were all of the patients who entered the trial properly accounted
for at its conclusion?
Yes
How large was the treatment effect? See table
7
How precise was the estimate of the treatment effect? See table
7
Can the results be applied in your context? (or to the local
population)
Yes
Were all clinically important outcomes considered? Yes
OvOvererall risk ofall risk of
bias/qualitybias/quality
assessment –assessment –
CASP RCT
checklist
Are the benefits worth the harms and costs? See key
points
StudyStudy
limitationslimitations
Short-term study (8 weeks)
The study did not include an active comparator
The study did not report on randomisation and blinding methods
It is unclear whether allocation was concealed
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CommentsComments a After randomisation the study protocol was amended and an upper age limit
of 16 years was set. Two participants were excluded from the efficacy
analysis, but were included in the safety analysis.b Problem drooling was defined as drooling in the absence of treatment such
that clothing became damp approximately 5–7 days per week. Of the
36 participants analysed for efficacy, 30 had cerebral palsy, 18 had oral
feeding problems and 15 used a tube for feeding.c This formulation of glycopyrronium bromide is available in the US as
Cuvposa. This is a different product to the licensed product available in the
UK (Sialanar), and there are differences in bioavailability.d Assessed at week 8 or at the last visit, using a 5-point scale, ranging from 1
(strongly agree) to 5 (strongly disagree) in response to the statement "This is a
worthwhile treatment".e Unclear if allocation was concealed.f Although the study stated that it was double-blind, it was not clear if both
investigators and clinicians providing care were blinded.
AbbreAbbreviations:viations: AUC, Area under curve; mTDS, Modified Teacher's Drooling Scale; RCT,
randomised controlled trial.
Results tablesResults tables
TTable 6 Mier et al. 2000able 6 Mier et al. 2000
GlyGlycopcopyrroniumyrronium PlaceboPlacebo AnalysisAnalysis
nna 2727 2727
Primary outcomePrimary outcome
Mean change in mTDS score from baseline to
mean maximum (best) score
From 7.52 at baseline
to 1.85
From 7.44
to 6.33
p<0.001
Selected secondary outcomesSelected secondary outcomes
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Page 24 of34
Mean mTDS score at lowest dose level to
highest dose level
1st dose level: 6.0
2nd dose level: 4.5
3rd dose level: 3.6
4th dose level: 2.6
After 4 weeks at
highest dose level: 2.3
Data not
reported
Not
reported
% of patients with improvement in mTDS
score of ≥4 points
1st dose level: 12%
2nd dose level: 38%
3rd dose level: 54%
4th dose level: 81%
Data not
reported
Not
reported
Safety and tolerSafety and tolerability outcomesability outcomes
nnbb 3939 3939
Patients reporting any adverse effect 25/36 (69%) 5/30
(17%)
Patients discontinued due to adverse effectsc 7/39 (18%) 1/39 (3%)
Behavioural changesd 9/39 (23%) 1/39 (3%)
Constipation 7/39 (18%) 0/39 (0%)
Excessive oral dryness 7/39 (18%) 0/39 (0%)
Urinary retention 5/39 (13%) 0/39 (0%)
Not
reported
a Efficacy population: only the participants who completed the study were included in the
efficacy analysis. No explanation or justification of this is provided by the authors.b Safety population for the individual adverse effects appears to include all randomised
participants. For 'any adverse effect' this appears to be reported for only 36/39 patients in
glycopyrronium group and 30/39 in the placebo group. The reason for this is not discussed in
the paper.c Of the 7 participants who stopped treatment in the glycopyrronium bromide group due to
adverse events, 4 stopped before the end of the first week.d Includes drowsiness, restlessness, hyperactivity, short attention span, frustration, irritability,
mood changes, temper outbursts, explosive behaviour, excessive sensitivity, seriousness,
sadness, frequent crying episodes, fearfulness.
AbbreAbbreviations:viations: mTDS, modified Teacher's Drooling Score.
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Page 25 of34
TTable 7 Zable 7 Zeller et al 2012aeller et al 2012a
GlyGlycopcopyrroniumyrronium PlaceboPlacebo AnalysisAnalysis
nna 1919 1717
Primary outcomePrimary outcome
Week 2: 52.6%
(10/19)
Week 2: 0%
(0/17)
Week 2:
p=0.0007
Week 4: 57.9%
(11/19)
Week 4:
17.6% (3/
17)
Week 4: p value
not reported
Week 6: 68.4%
(13/19)
Week 6:
11.8% (2/
17)
Week 6: p value
not reported
Responder rate (% of patients with
improvement in mTDS score of ≥3 points)
Week 8: 73.7%
(14/19)
Week 8:
17.6% (3/
17)
Week 8:
p=0.0011
Selected secondary outcomesSelected secondary outcomes
Mean improvement in mTDS score at 8
weeks (95% CI)
3.94 (2.97 to
4.91)
0.71 (−0.43
to 1.84)
p<0.0001
Proportion of investigators who considered
treatment worthwhileb
84.2% 41.2% p=0.0140
Proportion of parents/carers who
considered treatment worthwhileb
100% 56.3% p=0.0017
Safety and tolerSafety and tolerability outcomesability outcomes
nnc 2020 1818
Patients discontinued due to adverse events 1/20 (5%) 1/18 (6%)
Patients reporting a severe adverse event 4/20 (69%) 0/18 (0%)
Patients reporting any adverse event 20/20 (23%) 15/18
(83%)
Not reported
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Page 26 of34
Patients reporting an adverse event
considered to be treatment-related
15/20 (75%) 7/18 (39%)
Dry mouth 8/20 (40%) 2/18 (11%)
Constipation 6/20 (30%) 4/18 (22%)
Vomiting 6/20 (30%) 2/18 (11%)
Nasal congestion 6/20 (30%) 1/18 (5%)
Flushing 5/20 (25%) 3/18 (17%)
AE: urinary retention 3/20 (15%) 0/18 (0%)
a Efficacy population: modified ITT set, defined as all randomised participants who were within
the age range of the amended protocol and received at least one dose of study medication.b Assessment performed at week 8 or at the last visit.c Safety population: all randomised participants who received at least one dose of study
medication.
AbbreAbbreviations:viations: 95% CI, 95% confidence interval; AE, adverse effect; ITT, intention to treat;
mTDS, modified Teacher's Drooling Score.
ExExcluded studiescluded studies
Study referenceStudy reference Reason for eReason for exxclusionclusion
Blasco P A, and Stansbury J C (1996) Glycopyrrolate treatment of
chronic drooling. Archives of Pediatrics & Adolescent Medicine 150:
932–5.
Study not prioritised
(not the best available
evidence – open-label
study without a
comparator)
Davidson J, Wang C, Neiman R, and Cavanaugh P (2011) A Phase-3
multicenter, open-label study assessing the safety of glycopyrrolate
oral solution for the management of pathologic drooling in pediatric
patients with cerebral palsy or other neurologic conditions. Annals of
Neurology 70: S171.
Abstract only – results
of this study discussed
in Zeller et al. 2012b
Evatt M L (2011) Oral glycopyrrolate for the treatment of chronic
severe drooling caused by neurological disorders in children.
Neuropsychiatric Disease & Treatment 7: 543–7.
Not a relevant study
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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Page 27 of34
Montgomery J, McCusker S, Lang K, Grosse S, Mace A, Lumley R, and
Kubba H (2016) Managing children with sialorrhoea (drooling):
Experience from the first 301 children in our saliva control clinic.
International Journal of Pediatric Otorhinolaryngology 85: 33–9.
Study not prioritised
(not the best available
evidence – clinician
survey)
Parr J R, Buswell C A, Banerjee K, Fairhurst C, Williams J, O'Hare A,
Pennington L, British Academy of Childhood Disability Drooling
Study Development, and Group (2012) Management of drooling in
children: a survey of UK paediatricians' clinical practice. Child: Care,
and Health & Development, 38: 287-91.
Study not prioritised
(not the best available
evidence – clinician
survey)
Parr J R, Todhunter E, Pennington L, Cole M, Morrison J, Stocken D,
and Colver A. (2016) The drooling reduction intervention (DRI) trial:
Is hyoscine or glycopyrronium more effective and acceptable for the
treatment of drooling in children with neurodisability?. Archives of
Disease in Childhood 101: A55-A56.
Abstract only
Stern L M. (1997) Preliminary study of glycopyrrolate in the
management of drooling. Journal of Paediatrics & Child Health 33:
52–4.
Study not prioritised
(not the best available
evidence – preliminary
study using parent/
carer questionnaires)
Walshe M, Smith M, Pennington L (2012) Interventions for drooling
in children with cerebral palsy. Cochrane Database of Systematic
Reviews issue 11. Art. No.: CD008624. DOI: 10.1002/
14651858.CD008624.pub3
Study not prioritised
(not the best available
evidence –
meta-analysis that did
not include key studies)
TTerms used in this eerms used in this evidence summaryvidence summary
Modified TModified Teacher's Drooling Scale (mTDS)eacher's Drooling Scale (mTDS)
The modified Teacher's Drooling Scale (mTDS) is a 9-point scoring system measured by parents/
carers. Scores range from 1 to 9, with a higher score indicates more severe drooling:
1 = Dry: never drools
2 = Mild: only the lips are wet; occasionally
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3 = Mild: only the lips are wet; frequently
4 = Moderate: wet on the lips and chin; occasionally
5 = Moderate: wet on the lips and chin; frequently
6 = Severe: drools to the extent that clothing becomes damp; occasionally
7 = Severe: drools to the extent that clothing becomes damp; frequently
8 = Profuse: clothing, hands, tray, and objects become wet; occasionally
9 = Profuse: clothing, hands, tray, and objects become wet; frequently
Search strSearch strategyategy
Medline (1946-present)
Search date: 21st October 2016
1 Glycopyrrolate/ (835)
2 (glycopyrronium or glycopyrrolate or sialanar).tw. (960)
3 1 or 2 (1137)
4 Sialorrhea/ (1184)
5 (drool* or hypersalivat* or sialorrhea).tw. (1708)
6 4 or 5 (2156)
7 3 and 6 (43)
Medline in-process
Search date: 21st October 2016
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1 Glycopyrrolate/ (0)
2 (glycopyrronium or glycopyrrolate or sialanar).tw. (99)
3 1 or 2 (99)
4 Sialorrhea/ (0)
5 (drool* or hypersalivat* or sialorrhea).tw. (170)
6 4 or 5 (170)
7 3 and 6 (3)
Embase (1974 to 21th October 2016)
Search date: 21st October 2016
1 Glycopyrrolate/ (5454)
2 (glycopyrronium or glycopyrrolate or sialanar).tw. (1554)
3 1 or 2 (5585)
4 Sialorrhea/ (3973)
5 (drool* or hypersalivat* or sialorrhea).tw. (2723)
6 4 or 5 (5413)
7 3 and 6 (191)
8 limit 7 to English language (177)
9 *randomized controlled trial/ (37703)
10 *Randomization/ (2020)
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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11 *Placebo/ (55996)
12 *Crossover Procedure/ (3810)
13 (random or randomi* or randoml*).tw. (1137254)
14 rct*.tw. (43365)
15 (phase 4 or phase iv or phase 3 or phase iii).tw. (67806)
16 placebo*.tw. (246741)
17 (crossover* or (cross adj over*)).tw. (85155)
18 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 (1319359)
19 Nonhuman/ (4934829)
20 Human/ (17907880)
21 19 not (19 and 20) (3675982)
22 18 not 21 (1216959)
23 Clinical study/ (243890)
24 Case control study/ (121345)
25 Family study/ (24891)
26 Longitudinal study/ (104067)
27 Retrospective study/ (504524)
28 comparative study/ (736482)
29 Prospective study/ (380576)
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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30 Randomized controlled trials/ (121519)
31 29 not 30 (375968)
32 Cohort analysis/ (294471)
33 cohort analy*.tw. (7596)
34 (Cohort adj (study or studies)).tw. (175045)
35 (Case control* adj (study or studies)).tw. (101756)
36 (follow up adj (study or studies)).tw. (53183)
37 (observational adj (study or studies)).tw. (98943)
38 (epidemiologic* adj (study or studies)).tw. (88348)
39 (cross sectional adj (study or studies)).tw. (128781)
40 case series.tw. (65992)
41 prospective.tw. (618773)
42 retrospective.tw. (562957)
43 or/23-28,31-42 (2923018)
44 22 or 43 (3831639)
45 8 and 44 (39)
Cochrane library databases
Search date: 21st October 2016
#1 MeSH descriptor: [Glycopyrrolate] this term only 245
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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#2 glycopyrronium or glycopyrrolate or sialanar:ti,ab,kw (Word variations have been searched)
969
#3 #1 or #2 969
#4 MeSH descriptor: [Sialorrhea] this term only 71
#5 drool* or hypersalivat* or sialorrhea:ti,ab,kw (Word variations have been searched) 301
#6 #4 or #5 301
#7 #3 and #6 11
DeDevvelopment of this eelopment of this evidence summaryvidence summary
The evidence summary: process guide (2017) sets out the process NICE uses to select topics for
evidence summaries and details how the summaries are developed, quality assured and approved
for publication.
Expert advisers
Dr Anand Iyer, Consultant Paediatric Neurologist, Alder Hey Children's NHS Foundation Trust
Dr Karen Pysden, Consultant Paediatric Neurologist, Leeds Teaching Hospitals NHS Trust
Venkat Thiyagesh, Consultant in Paediatrics, Calderdale & Huddersfield NHS Foundation Trust
Declarations of interest
Anand Iyer: No interests declared
Karen Pysden: No interests declared
Venkat Thiyagesh: No interests declared
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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About this eAbout this evidence summaryvidence summary
Evidence summaries provide a summary of the best available published evidence for selected
new medicines, unlicensed medicines or off-label use of licensed medicines.
The summaries assess the strengths and weaknesses of the best available evidence to inform
health professionals and commissioners' decision-making.
This summary is not NICE guidanceThis summary is not NICE guidance.
ISBN: 978-1-4731-2285-7
Severe sialorrhoea (drooling) in children and young people with chronic neurological disorders: oralglycopyrronium bromide (ES5)
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